PROJECT SUMMARY/ABSTRACT Most cancers of the head and neck are squamous cell carcinomas (HNSCC) and the majority affects the oral cavity or pharynx. Tobacco use and alcohol consumption are the major risk factors and together account for approximately two-thirds of the cases. Oral infection with human papillomavirus (HPV) is an important independent risk factor for the development of oropharyngeal cancer (OPC); only 6% of other HNSCC sites are associated with HPV. Incidence of HPV-related OPC is increasing, most notably in the U.S. and Europe. Interestingly, and likely due to differences in etiology and related differences in tumor characteristics, HPV- positive [HPV(+)] tumors have a more favorable outcome than HPV-negative [HPV(-)] tumors. A recent large genome-wide association (GWA) study from this group identified multiple novel susceptibility loci for HNSCC, and in particular a strong role for the human leukocyte antigen (HLA) region in OPC. Further, recently completed tumor genome profiling efforts have provided important information on the somatic alterations present in HNSCC. However, only limited numbers of HPV(+) tumors were included and these studies have offered little insights into the clinical relevance of the identified alterations due to the limited nature of clinical and outcome data available. To improve understanding of the genetic factors involved in oral cancer (OC) and OPC risk and outcome, we will utilize samples and data from 5 well-annotated study populations to: (Aim 1) complete HPV analysis of 2,028 OPC cases in order to evaluate the relationship between germline variants, and in particular variants in the HLA region, and risk of HPV(+) OPC; (Aim 2) perform whole exome and targeted sequencing on 2,000 representative tumors (1,000 OCs, 1,000 OPCs) to further elucidate the driver mutations and potential therapeutic targets in OC and OPC, and to clarify potential mechanisms associated with lifestyle and infectious exposures for developing both cancers; and (Aim 3) utilize available outcome data on these 2,000 patients to evaluate the role of somatic alterations in OC and OPC in outcome, build prediction models for OC and OPC survival, and clarify the role of smoking in HPV(+) OPC outcome.